Hyperkalemic Periodic Paralysis Research Articles

Expression and Localization of Equine Tissue-Specific Divalent Ion-Transporting Channel Proteins

Divalent ions such as calcium, iron, and copper have roles in physiological functions such as maintaining ionic homeostasis. Ion channels, present in the cell membrane, control the flow of ions across the cell membrane. Hyperkalemic periodic paralysis, iron-deficiency anemia, and horse colic are related to ion channel malfunctions. Equine ion channels have not been studied as much as those in other species. In the present study, we focused on expression and localization of calcium, iron, and copper ion channels in equine duodenum, heart, kidney, liver, lung, ovary, uterus, and testis tissues. Gene and protein expressions were quantified by using real-time polymerase chain reaction and western blotting, respectively. Localization of each channel was identified via immunohistochemical analysis. Gene (mRNA) and protein levels of Nckx3 and Trpv2 were high in uterus tissue. Ferroportin (Ireg1) mRNA levels varied, but its protein level was notably high in liver. Hephaestin (Heph) mRNA level was high in duodenum, whereas its protein level was high in liver. Nckx3 was highly expressed in ovary, uterus, and testis. Trpv2 was expressed in duodenum, liver, lung, and kidney. Ferroportin was expressed in duodenum, liver, ovary, and uterus. Hephaestin was expressed in duodenum, ovary, and testis. Copper transporter 1 (Ctr1) was expressed in all tissues, whereas Atp7a was expressed in duodenum, kidney, and testis. Each protein was expressed in their respective structures, including gland, epithelium, and myocyte. Taken together, the regulation of each ion channel is important to secretion, absorption, and contraction in the various organ. The results of this study could form a basis for elucidating Nckx3-, Trpv2-, Ireg1-, Heph-, Ctr1-, and Atp7a-related diseases in horse.

P.231 - Chronic progressive myopathy in a young patient with hyperkalemic periodic paralysis

P.231 - Chronic progressive myopathy in a young patient with hyperkalemic periodic paralysis

GENETIC STRUCTURE OF HORSES POPULATION FOR THE GENES OF SCID AND HYPP

Objective: identification of carrier animals of the hereditary anomaly SCID and HYPP of the population of horses bred on breeding horse farms of the Republic of Belarus. Methods: genetic, biological. DNA diagnosis of genotypes in the gene severe combined immunodeficiency (SCID) and hyperkaliemic periodic paralysis (HYPP) was performed using polymerase chain reaction (PCR) and restriction fragment length polymorphism (RFLP) in the research laboratory «DNA Technology» of educational establishment «Grodno State Agrarian University». We tested 50 horses of different breeds, kept on different breeding horse farms of Belarus. DNA was isolated from buccal epithelium by perchlorate method with double purification (according to the method of Zinovieva). A study of the genetic structure of the horse population for hereditary anomalies of severe combined immunodeficiency and hyperkalemic periodic paralysis was performed using modern equipment. Amplification was carried out using the C1000 Touch thermal cycler (BioRad, USA). The visualization of the gel was carried out using the gel-documenting system Gel Doc XR + (Bio- Rad, USA). Main results. The use of modern methods for the genetic diagnosis of hereditary diseases of agricultural animals not only at birth to exclude from the process of reproduction of animal carriers of hereditary anomalies, but also reduces funding for their maintenance and cultivation. In the studies we used the PCR method based on the use of specific oligonucleotides with which the amplification of the necessary fragment of the 163 gene occurs in healthy individuals and 158 in the mutation carriers, which makes it possible to identify the hereditary SCID disease. We tested 50 animals of the upper and Arabian breeds, as well as horses with an admixture of Arabian blood, among which no carriers of the hereditary anomaly were found. In studies, the PCR-RFLP analysis method was used, based on the use of distinctive primers due to which the necessary fragment of the gene is amplified, which makes it possible to identify the hereditary HYPP disease. Amplified fragments were subjected to the action of restriction enzymes, with the help of which it is possible to determine the genotype of the animal under study. We tested 50 animals of the upper and Arabian breeds, as well as horses with an admixture of Arabian blood, among which no carriers of the hereditary anomaly were found. Conclusions. Severe combined immunodeficiency (SCID) is an autosomal recessive disease that occurs in humans, mice, horses and dogs. Carriers of this hereditary disease are born without visible anomalies, but after 2 weeks they become ill from any infection and die, since they can not develop an antigen-specific immune response. Hyperkaliemic periodic paralysis (HYPP) is an autosomal dominant disease that occurs in horses at the age of 2, when the animal begins, is strengthened to exercise. Symptoms of this disease are weakness of the muscles, periodic spasms, paralysis, which can lead to death. Presumably, there were no carriers of severe combined immunodeficiency in the Republic of Belarus, since breeding farms for breeding horses did not use biological material of Arabian and local breeds of horses for insemination. With subsequent importation of Arabian horses, as well as breeds that have an admixture of Arab blood, it is necessary to conduct DNA testing for the presence of severe combined immunodeficiency (SCID). According to the results of the conducted studies to identify the hereditary disease of hyperkalemic periodic paralysis (HYPP) in the horse population, no carriers were found, as well as sick animals. Presumably, there were no carriers of this disease on the territory of the republic, as evidenced by parallel studies conducted in other European countries, where no carrier or sick animal was found. This suggests that the disease was localized during the time, and also did not leave the territory of the American continent.

Spectrum of Nondystrophic Skeletal Muscle Channelopathies in Children

BackgroundThe nondystrophic skeletal muscle channelopathies are a group of disorders caused by mutations of various voltage-gated ion channel genes, including nondystrophic myotonia and periodic paralysis. MethodsWe identified patients with a diagnosis of muscle channelopathy from our neuromuscular database in a tertiary care pediatric center from 2005 to 2015. We then performed a retrospective review of their medical records for demographic characteristics, clinical features, investigations, treatment, and follow-up. ResultsThirty-three patients were identified. Seventeen had nondystrophic myotonia. Seven of them had chloride channelopathy (four Becker disease and three Thomsen disease). Warm-up phenomenon and muscle hypertrophy were common clinical manifestations in this subgroup. Ten patients had sodium channelopathy (four paramyotonia congenita and six other sodium channel myotonia). Stiffness of the facial muscles was an important presenting symptom, and eyelid myotonia was a common clinical finding in this subgroup. The majority of these patients had electrical myotonia. Mexiletine was effective in controlling the symptoms in patients who had received treatment. Sixteen children had periodic paralysis (four hyperkalemic periodic paralysis, eight hypokalemic periodic paralysis, and four Andersen-Tawil syndrome). Acetazolamide was commonly used to prevent paralytic attacks and was found to be effective. ConclusionsNondystrophic muscle channelopathies present with diverse clinical manifestations (myotonia, muscle hypertrophy, proximal weakness, swallowing difficulties, and periodic paralysis). Cardiac arrhythmias are potentially life threatening in Andersen-Tawil syndrome. Timely identification of these disorders is helpful for effective symptomatic management and genetic counseling.

Sodium Channelopathies of Skeletal Muscle.

The NaV1.4 sodium channel is highly expressed in skeletal muscle, where it carries almost all of the inward Na+ current that generates the action potential, but is not present at significant levels in other tissues. Consequently, mutations of SCN4A encoding NaV1.4 produce pure skeletal muscle phenotypes that now include six allelic disorders: sodium channel myotonia, paramyotonia congenita, hyperkalemic periodic paralysis, hypokalemic periodic paralysis, congenital myasthenia, and congenital myopathy with hypotonia. Mutation-specific alternations of NaV1.4 function explain the mechanistic basis for the diverse phenotypes and identify opportunities for strategic intervention to modify the burden of disease.

Pregnancy reduces severity and frequency of attacks in hyperkalemic periodic paralysis due to the mutation c.2111C>T in the SCN4A gene.

Pregnancy reduces severity and frequency of attacks in hyperkalemic periodic paralysis due to the mutation c.2111C>T in the SCN4A gene.

Effects of S906T polymorphism on the severity of a novel borderline mutation I692M in Nav 1.4 cause periodic paralysis.

Hyperkalemic periodic paralysis (HyperPP) is a dominantly inherited muscle disease caused by mutations in SCN4A gene encoding skeletal muscle voltage gated Nav 1.4 channels. We identified a novel Nav 1.4 mutation I692M in 14 families out of the 104 genetically identified HyperPP families in the Neuromuscular Centre Ulm and is therefore as frequent as I693T (13 families out of 14 HyperPP families) in Germany. Surprisingly, in 13 families, a known polymorphism S906T was also present. It was on the affected allele in at least 10 families compatible with a possible founder effect in central Europe. All affected members suffered from episodic weakness; myotonia was also common. Compared with I692M patients, I692M-S906T patients had longer weakness episodes, more affected muscles, CK elevation and presence of permanent weakness. Electrophysiological investigation showed that both mutants had incomplete slow inactivation and a hyperpolarizing shift of activation which contribute to membrane depolarization and weakness. Additionally, I692M-S906T significantly enhanced close-state fast inactivation compared with I692M alone, suggesting a higher proportion of inactivated I692M-S906T channels upon membrane depolarization which may facilitate the initiation of weakness episodes and therefore clinical manifestation. Our results suggest that polymorphism S906T has effects on the clinical phenotypic and electrophysiological severity of a novel borderline Nav 1.4 mutation I692M, making the borderline mutation fully penetrant.

Dichlorphenamide: A Review in Primary Periodic Paralyses.

Oral dichlorphenamide (Keveyis™) is a carbonic anhydrase inhibitor that is approved in the USA for the treatment of primary hyperkalaemic and hypokalaemic periodic paralyses and related variants. The efficacy and safety of dichlorphenamide in patients with primary periodic paralyses have been evaluated in four 9-week, randomized, double-blind, placebo-controlled, phase III trials [two parallel-group trials (HOP and HYP) and two crossover trials]. In two trials in patients with hypokalaemic periodic paralysis, dichlorphenamide was associated with a significantly (eightfold) lower paralytic attack rate and fewer patients with acute intolerable worsening compared with placebo. In two trials in patients with hyperkalaemic periodic paralysis, the attack rate was lower with dichlorphenamide than placebo, with this comparison reaching statistical significance in one trial (crossover) but not the other (HYP), although the attack rate was approximately fivefold lower with dichlorphenamide than placebo in the HYP trial. In 52-week, open-label extensions of the HOP and HYP trials, dichlorphenamide provided sustained efficacy in patients with hypokalaemic or hyperkalaemic periodic paralysis. Dichlorphenamide was generally well tolerated in all four phase III trials and during the extension trials; the most common adverse events were paraesthesia, cognitive disorders and dysgeusia. As the first agent to be approved in the USA for this indication, dichlorphenamide is a valuable treatment option for patients with primary hyperkalaemic or hypokalaemic periodic paralysis.

Mice with a Null Allele for NaV1.4 Exhibit Pseudo-Myasthenia, but are not Susceptibile to Periodic Paralysis

Functional analysis of disease-associated mutant NaV1.4 channels have revealed defects that often provide a mechanistic basis for derangements in sarcolemma excitability to produce the clinical phenotype. Loss-of-function mutations are less common and the pathogenic basis for muscle dysfunction is less clear than for the gain-of-function NaV1.4 mutations associated with myotonia, paramyotonia congenita or hyperkalemic periodic paralysis. Loss-of-function via enhanced inactivation (both fast and slow) accompanies other channel defects in hypokalemic periodic paralysis (HypoKPP) and is the primary defect in a rare form of congenital myasthenic syndrome. We explored whether a NaV1.4 loss-of-function created in a mouse would produce features of HypoKPP or myasthenia.A null allele of NaV1.4 was generated by excision of exon 12 (174 bp which encodes DIIS2-DIIS4). Heterozygous (+/-) mice were viable, but homozygous nulls (-/-) did not survive beyond P2. Spontaneous movement, feeding, and reproduction were normal in (+/-) mice. Voltage-clamp studies of dissociated fibers showed a 50% reduction of Ina in (+/-) animals. The Na current was completely blocked by 200 nM TTX, suggesting there was no compensatory upregulation of NaV1.5. In vitro contraction testing showed a right shift of the force- stimulus intensity curve and a prominent sag from the early peak force for submaximal stimulus intensities in (+/-) mice. Repetitive nerve stimulation did not elicit a decremental response in the compound muscle AP (CMAP) at baseline, but exposure to low-dose curare (0.5 uM) revealed a larger decrement for (+/-) than WT. These features are consistent with mild myasthenia. Challenge with low K did not diminish maximal tetanic force, nor did insulin & glucose infusion cause a decrease of CMAP amplitude, both of which were observed in our R669H HypoKPP mice.

Physiological basis for muscle stiffness and weakness in a knock-in M1592V mouse model of hyperkalemic periodic paralysis.

The mechanisms responsible for the onset and progressive worsening of episodic muscle stiffness and weakness in hyperkalemic periodic paralysis (HyperKPP) are not fully understood. Using a knock-in HyperKPP mouse model harboring the M1592V NaV1.4 channel mutant, we interrogated changes in physiological defects during the first year, including tetrodotoxin-sensitive Na(+) influx, hindlimb electromyographic (EMG) activity and immobility, muscle weakness induced by elevated [K(+)]e, myofiber-type composition, and myofiber damage. In situ EMG activity was greater in HyperKPP than wild-type gastrocnemius, whereas spontaneous muscle contractions were observed invitro. We suggest that both the greater EMG activity and spontaneous contractions are related to periods of hyperexcitability during which fibers generate action potentials by themselves in the absence of any stimulation and that these periods are the cause of the muscle stiffness reported by patients. HyperKPP muscles had a greater sensitivity to the K(+)-induced force depression than wild-type muscles. So, an increased interstitial K(+) concentration locally near subsets of myofibers as a result of the hyperexcitability likely produced partial loss of force rather than complete paralysis. NaV1.4 channel protein content reached adult level by 3weeks postnatal in both wild type and HyperKPP and apparent symptoms did not worsen after the first month of age suggesting (i) that the phenotypic behavior of M1592V HyperKPP muscles results from defective function of mutant NaV1.4 channels rather than other changes in protein expression after the first month and (ii) that the lag in onset during the first decade and the progression of human HyperKPP symptoms during adolescence are a function of NaV1.4 channel content.

Understanding the physiology of the asymptomatic diaphragm of the M1592V hyperkalemic periodic paralysis mouse.

The diaphragm muscle of hyperkalemic periodic paralysis (HyperKPP) patients and of the M1592V HyperKPP mouse model rarely suffers from the myotonic and paralytic symptoms that occur in limb muscles. Enigmatically, HyperKPP diaphragm expresses the mutant NaV1.4 channel and, more importantly, has an abnormally high Na(+) influx similar to that in extensor digitorum longus (EDL) and soleus, two hindlimb muscles suffering from the robust HyperKPP abnormalities. The objective was to uncover the physiological mechanisms that render HyperKPP diaphragm asymptomatic. A first mechanism involves efficient maintenance of resting membrane polarization in HyperKPP diaphragm at various extracellular K(+) concentrations compared with larger membrane depolarizations in HyperKPP EDL and soleus. The improved resting membrane potential (EM) results from significantly increased Na(+) K(+) pump electrogenic activity, and not from an increased protein content. Action potential amplitude was greater in HyperKPP diaphragm than in HyperKPP soleus and EDL, providing a second mechanism for the asymptomatic behavior of the HyperKPP diaphragm. One suggested mechanism for the greater action potential amplitude is lower intracellular Na(+) concentration because of greater Na(+) K(+) pump activity, allowing better Na(+) current during the action potential depolarization phase. Finally, HyperKPP diaphragm had a greater capacity to generate force at depolarized EM compared with wild-type diaphragm. Action potential amplitude was not different between wild-type and HyperKPP diaphragm. There was also no evidence for an increased activity of the Na(+)-Ca(2+) exchanger working in the reverse mode in the HyperKPP diaphragm compared with the wild-type diaphragm. So, a third mechanism remains to be elucidated to fully understand how HyperKPP diaphragm generates more force compared with wild type. Although the mechanism for the greater force at depolarized resting EM remains to be determined, this study provides support for the modulation of the Na(+) K(+) pump as a component of therapy to alleviate weakness in HyperKPP.

Prevalência da mutação causadora da paralisia periódica hipercalêmica em equinos da raça Quarto de Milha no Brasil

A paralisia periódica hipercalêmica (HYPP) é uma das principais enfermidades genéticas de caráter dominante que acometem cavalos da raça Quarto de milha (QM). A HYPP é causada por uma mutação pontual no gene SCN4A e, apesar de estar presente nos cavalos QM no Brasil, dados sobre a prevalência da HYPP são escassos. O objetivo deste trabalho foi verificar a prevalência da mutação responsável pela HYPP em cavalos QM, utilizados nas modalidades esportivas de rédeas (n=160), apartação (n=160), tambor e baliza (n=160), corrida (n=160) e conformação (n=101). Foram utilizados DNA sanguíneo dos 741 equinos; o teste genético para enfermidade foi padronizado e as amostras sequenciadas para identificação da mutação no gene alvo. A prevalência de HYPP na população amostrada foi de 4,2%, sendo que somente na linhagem de conformação foram identificados animais positivos (30,7%). Medidas de controle mais efetivas devem ser adotadas para diminuir a prevalência da HYPP.

Louis Ptáček receives the 2015 ASCI/Stanley J. Korsmeyer Award. Interview by Sarah Jackson.

Channelopathies encompass a diverse set of diseases that are caused by mutations in genes encoding ion channel subunits or their regulators. The first recognition of a channelopathy came from Louis Ptacek (Figure 1), whose lab cloned a mutated muscle sodium channel gene found in a family with hyperkalemic periodic paralysis. His subsequent work extends far beyond channelopathies, as he has continued studying a number of inherited, familial disorders. Ptacek’s research has identified a wide range of genes that are mutated in patients with migraine, epilepsy, cardiac arrhythmias, neurodegeneration, and circadian rhythm disorders. This year, the ASCI honors Ptacek’s outstanding work using human genetics to provide fundamental insights into the molecular mechanisms that drive disease pathophysiology. The JCI recently spoke with Ptacek about his path to success as a physician-scientist.

Diaphragm of Hyperkalemic Periodic Paralysis Mouse Has No Contractility Abnormality Compared to the Robust Abnormalities in EDL and Soleus

Hyperkalemic periodic paralysis (HyperKPP) is an autosomal dominant disease that is caused by mutations in the SCN4A gene that encodes for the Nav1.4 channel, the skeletal muscle isoform of Na+channels. HyperpKPP patients suffer from both myotonia and limb paralysis. The myotonia is the result of large membrane depolarization due to large Na+ influx through defective NaV1.4 channels, while the paralysis is caused by increases in extracellular [K+] [[K+]e). However; even though diaphragm also expresses Nav1.4 channels, HyperKPP patients rarely suffer from respiratory distress, as expected with any paralysis. Despite the fact that Na+ influxes through mutated NaV1.4 channels in diaphragm, soleus and EDL muscles from a HyperKPP mouse model are all significantly greater than in their WT counterparts, the HyperKPP diaphragm is the only muscles being spared from the K+‐induced paralysis. The lack of paralysis in diaphragm is not related to any significant increases in Na+ K+ ATPase α‐1 and α‐2 protein content, which actually only increased in HyperKPP EDL. Measurements of resting membrane potential (resting Em) and force demonstrated that the lower force generation in HyperKPP EDL and soleus compared to wild type muscles at different [K+]e was in part related to greater membrane depolarization when [K+]e was increased. However, for a given [K+]e or resting EM, HyperKPP diaphragm generated more force than WT diaphragm. It is proposed that another membrane component spares diaphragm from HyperKPP symptoms, possibly the Na+Ca2+ exchanger which can increase [Ca2+]i during contraction when [Na+]i is elevated as it does in cardiac muscle.

Accuracy of preimplantation genetic diagnosis in equine in vivo-recovered and in vitro-produced blastocysts.

Preimplantation genetic diagnosis has great potential in the horse, but information on evaluation of equine embryo biopsy samples is limited. Blastocysts were biopsied using a Piezo drill and methods for whole-genome amplification (WGA) investigated. Results for 33 genetic loci were then compared between biopsy samples from in vitro-produced (IVP) and in vivo-recovered (VIV) blastocysts. Under the experimental conditions described, WGA using the Qiagen Repli-g Midi kit was more accurate than that using the Illustra Genomiphi V2 kit (98.2% vs 25.8%, respectively). Using WGA with the Qiagen kit, three biopsy samples were evaluated from each of eight IVP and 19 VIV blastocysts, some produced using semen from stallions carrying the genetic mutations associated with the diseases hereditary equine regional dermal asthenia (HERDA), hyperkalemic periodic paralysis (HYPP) or polysaccharide storage myopathy 1 (PSSM1). Three of 81 biopsy samples (3.7%) returned 95% overall accuracy in IVP and VIV embryos, and this technique is suitable for use in a clinical setting.

Whole-Body Muscle MRI in Patients with Hyperkalemic Periodic Paralysis Carrying the SCN4A Mutation T704M: Evidence for Chronic Progressive Myopathy with Selective Muscle Involvement.

Background and PurposeHyperkalemic periodic paralysis (hyperKPP) is a muscle sodium-ion channelopathy characterized by recurrent paralytic attacks. A proportion of affected individuals develop fixed or chronic progressive weakness that results in significant disability. However, little is known about the pathology of hyperKPP-induced fixed weakness, including the pattern of muscle involvement. The aim of this study was to characterize the patterns of muscle involvement in hyperKPP by whole-body magnetic resonance imaging (MRI).MethodsWe performed whole-body muscle MRI in seven hyperKPP patients carrying the T704M mutation in the SCN4A skeletal sodium-channel gene. Muscle fat infiltration, suggestive of chronic progressive myopathy, was analyzed qualitatively using a grading system and was quantified by the two-point Dixon technique.ResultsWhole-body muscle MRI analysis revealed muscle atrophy and fatty infiltration in hyperKPP patients, especially in older individuals. Muscle involvement followed a selective pattern, primarily affecting the posterior compartment of the lower leg and anterior thigh muscles. The muscle fat fraction increased with patient age in the anterior thigh (r=0.669, p=0.009), in the deep posterior compartment of the lower leg (r=0.617, p=0.019), and in the superficial posterior compartment of the lower leg (r=0.777, p=0.001).ConclusionsOur whole-body muscle MRI findings provide evidence for chronic progressive myopathy in hyperKPP patients. The reported data suggest that a selective pattern of muscle involvement-affecting the posterior compartment of the lower leg and the anterior thigh-is characteristic of chronic progressive myopathy in hyperKPP.

Hyperkalemic Periodic Paralysis Caused by a Mutation in the Sodium Channel SCN4A Gene

Hyperkalemic periodic paralysis (HyperPP) is an autosomal dominant muscle sodium channelopathy characterized by recurrentepisode of reversible paralysis with concomitant hyperkalemia. The diagnosis of HyperPP is suggested by a history of attacks ofparalysis, positive family history, and the presence of myotonia. A 19-year-old man presented with recurrent generalized limbweakness since childhood. The paralysis often followed by fatigue, exercise, and fasting. His parents were clinically unaffectedand had never experienced paralytic symptoms. Electromyographic evaluation demonstrated myotonic discharge. Directsequencing of SCN4A exon 24 revealed a heterozygous A>G transition at nucleotide 4774, resulting in the substitution of amethionine by a valine at codon 1592 (Met1592Val). We report a patient with HyperPP confirmed by Met1592Val mutation inSCN4A gene.

Contractile abnormalities of mouse muscles expressing hyperkalemic periodic paralysis mutant NaV1.4 channels do not correlate with Na+influx or channel content

Hyperkalemic periodic paralysis (HyperKPP) is characterized by myotonic discharges that occur between episodic attacks of paralysis. Individuals with HyperKPP rarely suffer respiratory distress even though diaphragm muscle expresses the same defective Na(+) channel isoform (NaV1.4) that causes symptoms in limb muscles. We tested the hypothesis that the extent of the HyperKPP phenotype (low force generation and shift toward oxidative type I and IIA fibers) in muscle is a function of 1) the NaV1.4 channel content and 2) the Na(+) influx through the defective channels [i.e., the tetrodotoxin (TTX)-sensitive Na(+) influx]. We measured NaV1.4 channel protein content, TTX-sensitive Na(+) influx, force generation, and myosin isoform expression in four muscles from knock-in mice expressing a NaV1.4 isoform corresponding to the human M1592V mutant. The HyperKPP flexor digitorum brevis muscle showed no contractile abnormalities, which correlated well with its low NaV1.4 protein content and by far the lowest TTX-sensitive Na(+) influx. In contrast, diaphragm muscle expressing the HyperKPP mutant contained high levels of NaV1.4 protein and exhibited a TTX-sensitive Na(+) influx that was 22% higher compared with affected extensor digitorum longus (EDL) and soleus muscles. Surprisingly, despite this high burden of Na(+) influx, the contractility phenotype was very mild in mutant diaphragm compared with the robust abnormalities observed in EDL and soleus. This study provides evidence that HyperKPP phenotype does not depend solely on the NaV1.4 content or Na(+) influx and that the diaphragm does not depend solely on Na(+)-K(+) pumps to ameliorate the phenotype.

English

Hyperkalemic periodic paralysis (HYPP) is an autosomal co-dominant genetic disease of Quarter-mile horses which originated by a point mutation of the gene coding the sodium channel protein in the plasmatic membrane of muscular cells. The mutation affects both dominant homozygous and heterozygous animals with myotonia, unpredictable muscular paralysis, weakness and collapse. In some cases, death can occur due to paralysis of the hearth or respiratory muscles. Detection of affected animals can be achieved by a polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) test. Based on the fact that the mutation originated in the stallion “Impressive”, whose genetic material is known to have been used in Mexico, it is possible that HYPP have been disseminated among Mexican Quarter horses. Blood samples were obtained by random sampling from 51 Quarter horses and subjected to PCR-RFLP analysis. The results obtained showed 43 recessive homozygous (N/N, normal, 84.3%), seven heterozygous (N/H, affected, 13.7%) and one dominant homozygous (H/H, affected, 2%). Allelic frequencies found were N = 0.157 and n = 0.843. The total of 15.7% affected animals can be considered a relatively high frequency of the disease; therefore, molecular diagnosis of HYPP is recommended to prevent a further spread of the mutation among Mexican Quarter horses.   Key words: HYPP, quarter horse, PCR-RFLP, Mexico.

Muscle Disease

On the basis of strong research evidence, Duchenne muscular dystrophy (DMD), the most common severe childhood form of muscular dystrophy, is an X-linked recessive disorder caused by out-of-frame mutations of the dystrophin gene. Thus, it is classified asa dystrophinopathy. The disease onset is before age 5 years. Patients with DMD present with progressive symmetrical limb-girdle muscle weakness and become wheelchair dependent after age 12 years. (2)(3). On the basis of some research evidence,cardiomyopathy and congestive heart failure are usually seen in the late teens in patients with DMD. Progressive scoliosis and respiratory in sufficiency often develop once wheelchair dependency occurs. Respiratory failure and cardiomyopathy are common causes of death, and few survive beyond the third decade of life. (2)(3)(4)(5)(6)(7). On the basis of some research evidence, prednisone at 0.75 mg/kg daily (maximum dose, 40 mg/d) or deflazacort at 0.9 mg/kg daily (maximum dose, 39 mg/d), a derivative of prednisolone (not available in the United States), as a single morning dose is recommended for DMD patients older than 5 years, which may prolong independent walking from a few months to 2 years. (2)(3)(16)(17). Based on some research evidence, treatment with angiotensin-converting enzyme inhibitors, b-blockers, and diuretics has been reported to be beneficial in DMD patients with cardiac abnormalities. (2)(3)(5)(18). Based on expert opinion, children with muscle weakness and increased serum creatine kinase levels may be associated with either genetic or acquired muscle disorders (Tables 1 and 3). (14)(15)